ABSTRACT The obesity epidemic in the US continues nearly unabated, with increasingly alarming statistics regarding the parallel rise in other chronic diseases and the resulting increase in healthcare costs. The United States Preventive Services Task Force (USPSTF) recommends that primary care patients be screened for obesity and that those with a body mass index (BMI) ?30 kg/m2 receive an intensive, multicomponent behavioral weight loss intervention. However, the effectiveness of weight loss interventions implemented in primary care settings has been limited, with a recent meta-analysis showing only modest weight loss (1.2 kg) after 2 years. In addition, previously studied weight loss interventions in the US have largely failed to improve cardiovascular disease (CVD) event rates or total mortality. A growing body of evidence points to the health benefits of the Mediterranean (Med) diet, with strong observational and clinical trial data supporting the health benefits of this dietary pattern that includes generous consumption of high-quality fats and carbohydrates. Positive health outcomes include reduced CVD events and recent data suggests benefits for cancer prevention, cognitive health, and all-cause mortality. Many have raised the question whether a Med-style diet can be followed in the US (be acceptable to the American palate), particularly among low-income and minority populations who experience disproportionally high rates of CVD. Our research team has adapted a Med-style diet to the cultural preferences of the Southeast (?Med-South diet?) and this dietary pattern has achieved high levels of acceptability in low-income, primarily minority populations. In a large pre-post study evaluating the Med-South dietary intervention, we saw significant weight loss (3.6% of initial weight at 2 years) among participants with diabetes. What is missing is an explanatory (efficacy) randomized trial testing whether a primary care-based weight loss intervention emphasizing a healthful eating pattern (Med-South) can yield long-term weight loss and improved CVD risk profiles. Thus, we propose a randomized trial to assess a clinic-based, weight loss intervention promoting a Med- style dietary pattern. It will be conducted at 5 primary care sites (n=350 participants) representing a diverse spectrum of patients and settings. Patients with a BMI ? 30 kg/m2 will be enrolled and randomized to intervention or augmented usual care. To assure adequate subgroup representation, ? 40% of the sample will have diabetes, ? 40% will be male, and ? 40% will be African American. The intervention will be delivered in 3 phases over 24 months by research staff: Phase I (4 months) focuses on adopting a Med-style dietary pattern; Phase II (8 months) on weight loss; and Phase III (12 months) on weight loss maintenance. Outcomes will be assessed at 4, 12, and 24 months. The primary outcome is weight loss at 24 months. Secondary outcomes include change in physiologic, behavioral, and psychosocial measures. We will also assess implementation cost and the incremental cost-effectiveness of the intervention relative to the augmented usual care group.